Lipid Therapy, CAC, and Sex Differences

Mechanistic and Clinical Differences Between PCSK9 Inhibitors, Statins, and Bempedoic Acid in Coronary Artery Calcium Progression, Plaque Biology, and Sex-Specific Cardiovascular Risk

The Evolution of the Atherosclerotic Paradigm

Historically, atherosclerosisAtherosclerosis is the disease behind most heart attacks and many strokes. Cholesterol particles get stuck in the wall of an artery, the body sends immune cells to clean up, and over years that mess hardens into plaque. was conceptualized as a simplistic, linear process of cholesterolCholesterol is a waxy substance your body needs. It goes into cell walls, hormones, vitamin D, and the bile that digests your food. You would die without it. accumulation within the arterial wall leading to mechanical obstruction of blood flow. Contemporary research has fundamentally shifted this understanding toward an immunoinflammatory paradigm. Atherosclerosis is now characterized as a chronic inflammatory disease, initiated by the subendothelial deposition of apolipoproteinAn apolipoprotein is a protein attached to a fat-carrying particle in your blood. Fat and water don't mix, so these proteins act like a wrapper that lets fat travel safely through the bloodstream. B (apoBApoB is a protein that sits on the outside of every cholesterol particle that can get stuck in your artery wall and cause plaque. Each of those particles carries exactly one ApoB.)-containing lipoproteinsA lipoprotein is a tiny package that carries fat and cholesterol through your bloodstream. Since fat won't dissolve in water, it needs a protein wrapper to travel. such as low-density lipoprotein (LDLLDL, or low-density lipoprotein, is the main particle that carries cholesterol through your blood — and the main one that gets stuck in artery walls.), which undergo oxidative modification (ox-LDL) to trigger endothelial dysfunctionEndothelial dysfunction is when that thin lining stops doing its job well. Vessels don't widen properly, and the barrier gets leakier. and immune activation.^[1,2]

In this framework, disease progression is not merely a matter of plaque volumePlaque volume is the total physical amount of plaque in a stretch of artery, measured in cubic millimeters. but of plaquePlaque is the buildup of cholesterol, immune cells, scar tissue, and calcium inside an artery wall. composition and stability. The journey from initial endothelial injury to a life-threatening myocardial infarctionSee Heart Attack for the full entry. involves a complex interplay of lipid deposition, macrophageA macrophage is a large immune cell that swallows debris and invaders. The name literally means "big eater." infiltration, phenotypic switching of vascular smooth muscle cellsSmooth muscle cells make up the middle layer of an artery and control how much the vessel tightens or relaxes. (VSMCs), and the eventual formation of a necrotic coreThe necrotic core is the dead, mushy center of an advanced plaque, built from immune cells that ate trapped cholesterol and then died in place..^[1,3] The final clinical manifestation—whether stable anginaAngina is chest discomfort that happens when the heart muscle isn't getting enough oxygen. People describe it as pressure, tightness, squeezing, or burning, and it can spread to the arm, neck, or jaw. or an acute coronary syndromeAcute coronary syndrome (ACS) is the umbrella term for any sudden drop in blood flow to the heart — from unstable angina to a full heart attack — caused by a plaque suddenly rupturing or eroding. (ACS)—is dictated by the mechanical integrity of the plaque’s fibrous capThe fibrous cap is the tough layer of tissue covering a plaque, separating its greasy core from the bloodstream. and the biological state of its calcificationCalcification is when calcium gets deposited into a plaque, turning part of it hard and bony..^[4,9]

The standard non-invasive tool for assessing atherosclerotic burden has long been the coronary artery calcium (CAC)Coronary artery calcium is a measure of calcified plaque deposits in the walls of the coronary arteries, quantified by CT scan and expressed as an Agatston score; higher scores indicate greater cumulative plaque burden and predict future cardiovascular events. score. The Agatston scoreThe Agatston score is the specific formula used to turn a calcium CT scan into a single number, weighting each calcium deposit by how dense and how large it is. is one of the most powerful predictors of future cardiovascular events, yet its relationship with pharmacological intervention is more complex than it first appears.^[5] The emergence of intensive lipid-lowering therapies—including high-intensity statinsA high-intensity statin is a dose expected to cut LDL by 50 percent or more — in practice, higher doses of atorvastatin or rosuvastatin., PCSK9 inhibitorsA PCSK9 inhibitor is a medicine that blocks that cholesterol-destroying protein, leaving more docking ports available to clear particles from the blood., and bempedoic acidBempedoic acid is a cholesterol-lowering pill that works in the liver, at a point just before where statins act.—has highlighted meaningful differences in how these agents influence plaque biology and radiographic calcification, with important implications for how CAC scores are interpreted in treated patients.^[5,9,13]

The Statin–CAC Paradox: Plaque Stabilization and Calcium Densification

Observational cohorts have frequently shown that statinA statin slows the enzyme your liver uses to make cholesterol. Your liver responds by pulling more cholesterol out of your blood, which is where the real benefit comes from. users have higher Agatston scores over time compared with matched untreated individuals, even as their rate of clinical events falls markedly—a pattern sometimes called the “statin–CAC paradox.”^[5,7] Randomized controlled trialA randomized controlled trial assigns people to a treatment or a comparison group purely by chance, then follows both groups. data on this question are less consistent: heterogeneous CAC quantification methods and limited follow-up durations mean that RCTs have not demonstrated a statistically significant overall effect of statins on CAC progression.^[7] The strongest and best-supported imaging signal is not blanket acceleration of calcification but a shift in the nature of the calcium itself: statins are associated with decreases in low-attenuation and fibro-fatty plaque components alongside greater progression of high-density calcium phenotypes.^[5,6,45]

Mechanistic Basis of Plaque Stabilization

The “healing hypothesis” proposes that intensive lipid loweringLipid lowering means reducing the harmful, ApoB-carrying particles in your blood — through food, medication, or both. transforms unstable, lipid-rich, inflamed plaques into more fibrotic and mechanically stable lesionsIn cardiology, a lesion refers to a discrete area of atherosclerotic plaque narrowing a coronary artery, typically described by the percentage of luminal obstruction it causes. The article describes four residual lesions too small in vessel diameter to accept a stent after the most critical one was treated..^[5,8] As lipid and necrotic components are resolved, the vessel wall undergoes remodeling characterized by deposition of dense calcium that serves as structural reinforcement around the necrotic core, reducing mechanical stress on the fibrous cap and sequestering pro-thrombotic material from the bloodstream.^[8]

Serial CCTA data from the PARADIGM studyPARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging) is a serial CCTA registry study that tracked changes in coronary plaque composition over time, providing key evidence that statin therapy shifts plaques toward denser, more stable calcium phenotypes. support this model: statin therapy was associated with reductions in low-attenuation and fibro-fatty plaque and with greater progression of high-density calcified plaqueCalcified plaque is the hardened, calcium-filled part of a plaque. It shows up brightly on a CT scan, which is what a calcium scan measures., while the increase in overall calcified plaque volume was attenuated in lesions without lipid-rich components.^[45] A 2025 serial noncontrast CT study similarly found a statin-associated shift toward denser calcium strata in asymptomatic individuals.^[6] These findings provide a more precise characterization than simply stating that statins accelerate CAC progression.

In some patients, therefore, a rising Agatston score under effective lipid-lowering may partly reflect plaque maturation and densification rather than new atherogenesisAtherogenesis is the step-by-step process of a plaque forming.. However, serial CAC alone cannot reliably distinguish healing from ongoing disease activity on an individual-patient basis, and this interpretation should not be generalized without supporting clinical context.^[5]

Proposed Mechanisms: Vitamin K2 and Macrophage Pathways

Several mechanisms have been proposed to explain statin-associated calcium densification. One hypothesis involves inhibition of Vitamin K2Vitamin K2 (menaquinone) is a fat-soluble cofactor required to activate Matrix Gla-protein, which inhibits vascular calcification; statin therapy may reduce vitamin K2 bioavailability as a byproduct of mevalonate pathway suppression, potentially influencing how calcium is deposited in plaques. synthesis: Vitamin K2 is a cofactor for Matrix Gla-protein (MGP)Matrix Gla-protein is a vitamin K–dependent protein secreted by vascular smooth muscle cells that acts as a physiological inhibitor of arterial calcification; it requires carboxylation by vitamin K2 to be active., a physiological inhibitor of vascular calcification, and reduced Vitamin K2 bioavailability could theoretically remove a brake on the calcification process.^[7,8] Macrophage-mediated pathways that normally inhibit calcium deposition may also be suppressed. These remain mechanistic hypotheses drawn largely from preclinical work; they have not been established as dominant pathways in randomized human studies, and the statin-calcification literature explicitly frames this biology as still-disputed.^[7,8]

Table 1: Plaque Characteristics: Untreated Progression vs. Statin-Associated Remodeling

Feature	Untreated Disease Progression	Statin-Associated Remodeling
Plaque Composition	High lipid content, large necrotic core	Fibrotic, reduced lipid-rich components
Calcium Phenotype	Spotty, low-density microcalcificationMicroscopic calcium deposits within atherosclerotic plaque that fall below the resolution threshold of conventional CT; unlike dense macrocalcification, microcalcifications can generate mechanical stress within the fibrous cap and increase plaque rupture susceptibility.	Associated shift toward denser, more coalescent calcium strata
Fibrous Cap	Thin, inflamed, rupture-prone	Thickened, stable, reduced mechanical stress
Agatston Score Trend	Rising due to new lesion formation	May rise due to calcium densification; requires careful clinical interpretation
Clinical Risk	Highly elevated	Significantly reduced despite possible calcium scoreA calcium score (coronary artery calcium score) is a number derived from a CT scan that quantifies the total amount of calcified plaque in the coronary arteries; a score of zero indicates no detectable calcified plaque, while higher scores reflect greater plaque burden and elevated cardiovascular risk. rise

PCSK9 Inhibitors: Plaque Regression and Fibrous Cap Restoration on Background Statin Therapy

PCSK9PCSK9 is a protein made by your liver that destroys the docking ports your liver uses to pull cholesterol out of your blood. inhibitors such as evolocumabEvolocumab is an injectable cholesterol medicine in the PCSK9 inhibitor family, usually given every two to four weeks. and alirocumabAlirocumab, sold as Praluent, is an injectable antibody that blocks PCSK9, given every two to four weeks. achieve profound reductions in LDL-C by preventing hepatic degradation of low-density lipoprotein receptors (LDLRLDLR is the gene that builds the LDL receptor, the docking port your liver uses to pull cholesterol particles out of circulation.).^[10,11] The principal plaque-imaging trials demonstrated meaningful regression of atheromaAtheroma is another word for the fatty deposit inside an artery wall — essentially a synonym for plaque, used more often in research writing. volume and improvement in plaque morphology incremental to background statin therapy. Throughout this section it is important to note that GLAGOVGLAGOV added a PCSK9 inhibitor to statin therapy and measured coronary plaque with intravascular ultrasound before and after., HUYGENSHUYGENS used optical coherence tomography — a very high-resolution imaging catheter — to see whether a PCSK9 inhibitor changed plaque structure after a heart attack., and PACMAN-AMIPACMAN-AMI gave a PCSK9 inhibitor to patients immediately after a heart attack and imaged their non-culprit arteries with three different catheter techniques. all studied PCSK9 inhibition added to statins; their findings cannot be straightforwardly attributed to PCSK9 inhibition as a standalone drug-class effect. Direct evidence on CAC progression with PCSK9 inhibitors is limited and less mature than plaque-regression evidence from IVUS and OCT trials; available data include a small randomized secondary analysis of alirocumab-plus-statin therapy showing attenuated CAC progression versus standard statin-based care, but no large dedicated CAC progression trial comparable to GLAGOV or HUYGENS has been reported.^[14,15]

Plaque Regression and Fibrous Cap Thickening

The GLAGOV trial demonstrated that evolocumab added to statin therapy produced significant regression of coronary atheroma volume: a −0.95% nominal change in percent atheroma volumePercent atheroma volume, or PAV, is the share of an artery segment taken up by plaque rather than open channel. (PAV) versus a +0.05% increase in the placeboA placebo is a dummy treatment — a sugar pill or a saline injection — given so researchers can tell what a real drug actually does. group (P<0.001), with 64.3% of evolocumab-treated patients demonstrating PAV regression versus 47.3% in the placebo group (P<0.001). Mean achieved LDL-C was 36.6 mg/dL versus 93.0 mg/dL in the placebo group.^[14]

The HUYGENS trial, using serial optical coherence tomographyOptical coherence tomography, or OCT, threads a light-based probe into a coronary artery. It sees roughly ten times finer detail than ultrasound. (OCT) following acute myocardial infarction, showed that evolocumab produced significantly greater minimum fibrous cap thickness increase (+42.7 μm vs. +21.5 μm; P=0.015) and maximum lipid arc reduction (−57.5° vs. −31.4°; P=0.04) compared with placebo.^[15]

The PACMAN-AMI trial demonstrated that alirocumab initiated within 24 hours of acute myocardial infarction produced significantly greater regression in percent atheroma volume (PAV −2.13% vs. −0.92%, P<0.001) and greater reduction in normalized total atheroma volume (−26.12 mm³ vs. −14.97 mm³), as well as greater fibrous cap thickening, compared with statin monotherapy.^[11]

Vascular Biology: Established and Emerging Signals

Preclinical studies have identified potential LDLR-independent effects of PCSK9 on atherogenesis, including inhibition of monocyte adhesion to stimulated human coronary arteryAn artery is a blood vessel that carries blood away from the heart to the rest of the body. endothelial cellsThe thin layer of cells lining the inner surface of all blood vessels; they regulate vascular tone, prevent clotting, and control the passage of substances into the artery wall — and their dysfunction is an early, critical step in atherosclerosis. (HCAECs) via the VCAM-1VCAM-1 is a sticky molecule that appears on an inflamed vessel lining and grabs passing white blood cells so they can burrow into the wall. and ICAM-1ICAM-1 is a molecule that appears on the surface of the blood vessel lining and acts like Velcro, catching passing immune cells. pathways.^[12,16] In large cardiovascular outcome trials, however, PCSK9 inhibition has generally shown minimal change in hsCRP, indicating that the clinically established primary mechanism of benefit is profound apoB/LDL lowering rather than a systemic anti-inflammatory effect. Pleiotropic or local vascular effects suggested by preclinical work may contribute, but this should not be overstated given the largely neutral hsCRP signal in human trial data.^[17]

Lipoprotein(a): An Important Independent Risk Factor

A meaningful advantage of PCSK9 inhibitors is their ability to lower Lipoprotein(a)Lipoprotein(a), written Lp(a) and said "L-P-little-a," is an LDL-like particle with an extra sticky protein attached. [Lp(a)], an independent and genetically determined cardiovascular risk factorA risk factor is something that raises your chance of developing a disease — high cholesterol particles, high blood pressure, smoking, diabetes, family history. largely unaffected by statin therapy.^[10] PCSK9 inhibitors reduce Lp(a) by approximately 25–27% (median 26.9% in the FOURIERFOURIER tested evolocumab, a PCSK9 inhibitor, in patients who already had cardiovascular disease and were on statins. evolocumab cohort). The relationship between Lp(a) levels and CAC burden is inconsistent across studies; Lp(a) and CAC appear to be independently informative risk markers rather than tightly correlated measures. Clinicians should therefore distinguish the robust evidence that elevated Lp(a) is an independent ASCVD risk factor from the weaker and less consistent evidence that Lp(a) directly predicts CAC burden.^[10,17]

Bempedoic Acid: Proven Outcomes, Limited Plaque Imaging Evidence

Bempedoic acid is an oral ATP citrate lyase (ACL) inhibitor that acts upstream of HMG-CoA reductaseHMG-CoA reductase is the rate-limiting enzyme in the liver's cholesterol biosynthetic (mevalonate) pathway; statins work by competitively blocking it, reducing the liver's own cholesterol production and prompting it to pull more LDL out of the bloodstream. in the cholesterol biosynthesis pathway.^[19,23] As a prodrugA prodrug is a pharmacologically inactive compound that is converted into its active form by metabolic processes after administration; bempedoic acid is a prodrug activated specifically in the liver, which is why it avoids causing muscle side effects seen with statins., it is converted into its active metabolite, bempedoyl-CoA, by the enzyme very long-chain acyl-CoA synthetase 1 (ACSVL1). This activating enzyme is expressed in the liver but is absent in skeletal muscle, providing the mechanistic basis for the drug’s low incidence of muscle-related adverse effects and making it a valuable option for statin-intolerant patients.^[20,23]

Cardiovascular Outcomes: The CLEAR Trials

The CLEAR OutcomesCLEAR Outcomes was a large trial that tested bempedoic acid in people who couldn't tolerate statins, to see whether it lowered heart attack and stroke risk the way statins do. trial established clinical efficacy in high-risk, statin-intolerant patients.^[21] Over a median follow-up of 3.4 years, bempedoic acid achieved a 21.1% placebo-corrected reduction in LDL-C and a statistically significant 13% relative riskRelative risk compares two groups: this group had 30 percent fewer heart attacks than that group. reduction in the primary MACE-4MACE-4 (Major Adverse Cardiovascular Events, 4-component) is a composite clinical endpoint comprising cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization, used as the primary endpoint in the CLEAR Outcomes trial. endpoint [HR 0.87, 95% CI 0.79–0.96; P=0.004].^[21] A prespecified total-event analysis demonstrated a 20% reduction in total MACE-4 events [HR 0.80, 95% CI 0.72–0.89; P<0.001].^[22]

Table 2: CLEAR Outcomes Trial: Cardiovascular Endpoint Summary (Nissen et al., NEJM 2023; JAMA 2024)

Outcome (CLEAR Outcomes)	HR	95% CI
MACE-4 — Primary Endpoint	0.87	0.79–0.96  (P = 0.004)
MACE-3 (CV Death / MI / StrokeA stroke happens when blood flow to part of the brain stops, either from a blockage or from bleeding.)	0.85	0.76–0.96
Fatal or Nonfatal MI	0.77	0.66–0.91
Coronary RevascularizationRevascularization is a medical or surgical procedure—such as coronary artery bypass grafting or percutaneous coronary intervention—performed to restore blood flow through a blocked or narrowed coronary artery, addressing the physical obstruction rather than the underlying atherogenic process.	0.81	0.72–0.92
Total MACE-4 Events (prespecified)	0.80	0.72–0.89  (P < 0.001)

Inflammation, Mechanism, and Imaging Evidence

A distinguishing feature of bempedoic acid is its consistent reduction of hsCRP: a 22% placebo-corrected median reduction was observed at 6 months in CLEAR Outcomes.^[19,21] Activation of the AMP-activated proteinProtein is the nutrient your body uses to build and repair muscle and tissue. kinase (AMPK) pathway has been proposed as a contributing cellular mechanism, based primarily on preclinical and mechanistic review data.^[20,23] More recent work suggests the drug’s biology may be more complex than initially characterized, with preliminary evidence of potential direct PPARα activation; these mechanistic questions remain under active investigation and should not be presented as settled biology.

Bempedoic acid has proven outcomes benefit and hsCRP lowering in statin-intolerant patients, but its direct effects on coronary plaque morphology remain largely unproven pending dedicated imaging trials.^[24] The only published plaque-imaging evidence is a single case report describing shrinkage of low-attenuation plaqueLow-attenuation plaque is the very darkest, fattiest plaque on a CT scan — soft enough that X-rays pass through it easily. with long-term bempedoic acid monotherapy—a hypothesis-generating observation, not proof of a plaque-regression class effect. A phase 3 imaging trial registered in 2026 evaluates the combination of bempedoic acid, ezetimibeEzetimibe is a pill that blocks your intestines from absorbing cholesterol., and high-intensity statin therapy on coronary plaque; its design tests triple combination therapy rather than bempedoic acid in isolation, and results have not yet been reported.

Limitations and Blind Spots of CAC = 0: Moving Beyond a Binary Interpretation

The observation that a CAC score of 0 predicts very low 10-year cardiovascular riskTen-year cardiovascular risk is a calculated probability—expressed as a percentage—that an individual will experience a major cardiovascular event such as a heart attack or stroke within the next decade, estimated using validated equations that factor in age, sex, blood pressure, cholesterol, diabetes status, and smoking; current guidelines reserve primary-prevention aspirin consideration for adu…—the “power of zero”—has established CAC as a useful gatekeeper in risk stratification.^[25,27,29] CAC = 0 is a genuinely powerful short-term negative risk marker in most clinical settings. However, it has important and well-characterized blind spots that require careful interpretation, particularly in symptomatic patients, younger individuals, and women in mid-life.^[30]

Non-Calcified Plaque: The Underdetected Component

A CAC score of 0 does not exclude coronary artery diseaseCoronary artery disease is plaque buildup in the arteries feeding the heart muscle.. Non-calcified plaqueNon-calcified plaque is the soft, fatty portion of a plaque that has not hardened with calcium. It shows up dark on a CT scan. (NCP), which is lipid-rich and highly vulnerable to rupture, is entirely invisible on non-contrast CT.^[25,28] Studies using CCTA have shown that approximately 15–17% of low-to-intermediate-risk individuals with CAC = 0 have detectable atherosclerosis, with roughly 3.5% harboring obstructive disease (>50% stenosisStenosis is narrowing — usually described as a percentage, like a 70 percent blockage.) despite a zero calcium scoreA zero calcium score means a CT scan found no hardened plaque in your heart's arteries at all..^[28,30]

In a diverse symptomatic Montefiore cohort analyzed by Rozanski et al., a zero CAC score retained very high negative predictive value for obstructive coronary disease and near-term adverse events, and only a small percentage of CAC = 0 patients—approximately 7%—had detectable noncalcified plaqueAtherosclerotic deposits within artery walls that have not yet undergone calcification; sometimes called 'soft' plaque, these lesions are lipid-rich and structurally unstable, making them more prone to rupture and acute thrombosis than calcified plaque. on CCTA.^[30] Separate prospective data from stable-chest-pain populations likewise show very low MACE event rates when CAC = 0, though obstructive CAD is not completely excluded. These data together confirm that CAC = 0 is a genuinely powerful short-term reassurance signal, while still leaving a clinically meaningful minority with non-calcified plaque that calcium scoring cannot detect.

The mechanisms of clinical events in individuals with CAC = 0 typically involve rupture or erosion of non-calcified lesions, systemic inflammationInflammation is your immune system's response to injury or something it treats as an invader. It brings swelling, heat, and cleanup cells., or coronary microvascular dysfunctionMicrovascular dysfunction is disease in the smallest blood vessels of the heart, too small to see on any angiogram..^[27,31] Plaque erosionPlaque erosion is when the lining over a plaque simply wears away and a clot forms, without the cap tearing open.—disruption of the endothelial surface over a lipid-rich non-calcified plaque—is particularly common in women and younger individuals.^[27]

Prevalence Estimates Depend Critically on Cohort and Method

In the SCAPISSCAPIS (Swedish CArdioPulmonary bioImage Study) is a large population imaging study of more than 25,000 Swedish adults aged 50 to 64 with no known coronary artery disease, which used coronary CT angiography to detect atherosclerosis in 42 percent of participants and significant stenosis in about 5 percent. (Swedish Cardiopulmonary Bioimage Study), among middle-aged adults from the general population with CAC = 0, approximately 5.5% had any coronary plaque detectable on CCTA and 0.4% had significant stenosis.^[29] The frequently cited 9.2% plaque-prevalence figure from SCAPIS applies specifically to the subgroup with CAC = 0 and intermediate 10-year ASCVD risk—an important distinction, because applying this conditional estimate to the entire CAC-zero general population would materially overstate disease prevalence.^[29]

AI-QCT registries of symptomatic patients referred for clinical CCTA report substantially higher plaque detection rates in CAC = 0 individuals—ranging from approximately 54% to 95% in some selected cohorts.^[26] These figures are not generalizable to screening populations; they reflect the higher pre-test probabilityThe estimated likelihood that a patient has a particular condition before a diagnostic test is performed, based on symptoms, risk factors, and clinical context; in CAC interpretation, a symptomatic patient has a higher pre-test probability of coronary disease, so a zero score still leaves meaningful residual risk. of clinical referral cohorts as well as variation in AI-QCT protocols, thresholds, and definitions across studies. Prevalence estimates from symptomatic, asymptomatic, general-population, and AI-QCT registry studies should not be combined without careful population-specific stratification.^[30]

Table 3: Prevalence of Non-Calcified Plaque in CAC = 0 Patients: Context-Dependent Estimates Across Study Populations

Study / Cohort	Population	Key Finding for CAC = 0 Patients
Cheng et al.	Low to intermediate risk, asymptomatic	~16% with detectable non-calcified plaque on CCTA
Rubinshtein et al.	Symptomatic	~14.5% with plaque; ~3% with obstructive disease
Rozanski et al. (JCCT 2023)	Symptomatic stable chest pain, diverse population	~7% NCP on CCTA; very high NPV for obstructive disease and near-term events; diverse symptomatic Montefiore cohort
SCAPIS (Bergström et al.)	Middle-aged general population	~5.5% any plaque overall; ~9.2% specifically in the CAC=0 + intermediate-risk subgroup [29]
AI-QCT registries (selected clinical CCTA cohorts)	Symptomatic / high pre-test probability	54–95%: highly dependent on cohort selection, referral indication, and AI-QCT protocol. Not generalizable to screening populations [26]

Sex-Specific Cardiovascular Risk and Plaque Biology

Women exhibit important differences in the presentation and pathophysiology of atherosclerotic cardiovascular diseaseCardiovascular disease is the umbrella term for problems with the heart and blood vessels, including heart attacks, strokes, and blocked leg arteries. (ASCVD) compared with men. Women generally develop clinically manifest coronary artery disease approximately a decade later than men, a phenomenon largely attributed to the vasoprotective effects of endogenous estrogenEstrogen is a hormone, present at much higher levels in women before menopause, that affects blood vessels, cholesterol, and bone..^[37,39]

The Protective Role of Estrogen and the Menopause Transition

Estrogen maintains vascular health through multiple pathways: it promotes endothelium-dependent vasodilation by stimulating nitric oxideNitric oxide is a gas your blood vessel lining makes to tell the vessel to relax and widen. (NO) and prostacyclin synthesis, inhibits vascular smooth muscle cell contraction and proliferation, and exerts anti-inflammatory effects on the vessel wall.^[35,38] Estrogen also maintains more favorable lipid profilesA blood test panel that measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, used to assess cardiovascular risk and monitor the effect of dietary or drug interventions. throughout the premenopausal years.^[35]

The menopauseMenopause is when a woman's periods stop permanently, usually around age 51, as estrogen levels fall. transition is associated with a precipitous decline in circulating estradiol, triggering accelerated vascular agingThe progressive structural and functional deterioration of arteries over time, characterized by loss of elasticity, increased stiffness, and accumulation of microscopic damage that makes arterial walls more susceptible to lipid deposition and chronic inflammation.. This shift produces measurable reductions in endothelial functionThe ability of the inner lining of blood vessels to regulate vascular tone, inflammation, and clotting; healthy endothelial cells release nitric oxide to keep arteries relaxed and resistant to plaque formation. as assessed by flow-mediated dilation (FMD)Flow-mediated dilation is a non-invasive ultrasound measurement of how much a conduit artery — typically the brachial artery — widens in response to increased blood flow, serving as a marker of endothelial nitric oxide signaling and endothelial function., increased systemic oxidative stressOxidative stress is an imbalance between damaging reactive molecules and the body's ability to neutralize them., and progressive worsening of arterial stiffnessArterial stiffness is a measure of how much an artery's wall resists expansion with each pulse of blood; it increases with age as elastin is lost and collagen accumulates, and manifests clinically as a rising systolic blood pressure alongside a falling or stable diastolic blood pressure after about age 60., blood pressureBlood pressure is the force of blood pushing against your artery walls. It is written as two numbers, like 120/80. The top number is the pressure when your heart squeezes, the bottom is when it relaxes., and atherogenic dyslipidemiaAtherogenic dyslipidemia is a lipid pattern characterized by elevated triglycerides, low HDL cholesterol, and an increased proportion of small, dense LDL particles; it is commonly seen with insulin resistance, visceral obesity, and sedentary behavior, and is associated with accelerated atherosclerosis..^[34,36] FMD in late postmenopausal women is approximately 50% lower than in premenopausal women of similar age, with the most significant decline occurring during the perimenopausal transition.^[34]

Risk Acceleration After Menopause

As women enter their 60s, cardiovascular risk accelerates markedly, with CVD incidence approaching that of age-matched men.^[37,38] Longitudinal data from the Healthy Women Study show that among postmenopausal women with a baseline CAC of 0, approximately 33% develop new, incident calcification over a subsequent 6-year period, with premenopausal LDL-C and HDL-C as strong predictors.^[39]

Early Menopause and Long-Term Risk

Women who experience early menopause (EM, defined as menopause before age 45) face substantially greater long-term cardiovascular risks. In the Multi-Ethnic Study of Atherosclerosis (MESA)A large prospective cohort study of adults initially free of cardiovascular disease that has provided foundational data on coronary artery calcium scoring, demonstrating a strong graded association between CAC burden and future coronary events and validating the risk implications of a CAC score of zero., more than half of postmenopausal women with early menopause had a baseline CAC score of 0.^[40] Among those women with CAC = 0, 10-year ASCVD incidence was low-to-borderline, yet those with early menopause had significantly higher 15-year risk than those without (adjusted HR 1.96, 95% CI 1.26–3.04).^[40] This illustrates the core diagnostic problem: the same CAC = 0 result that appears reassuring at 10 years can mask a substantially elevated long-term risk trajectory in women with early menopause, driven by prolonged estrogen deficiency that accelerates subclinical plaque accumulation after the initial scan.

Systematic meta-analyses confirm that early menopause is independently associated with a 50–60% increase in lifetime coronary heart diseaseCoronary heart disease is the narrowing or blockage of the arteries that supply blood to the heart muscle, caused by the buildup of atherosclerotic plaque; it is the leading cause of heart attack and cardiac death worldwide. risk, an effect only partially attenuated by traditional risk factor adjustment.^[41]

Sex Differences in Plaque Morphology and Detection

Women generally have lower absolute CAC burden than men and, in several cohorts, lower absolute plaque burdenPlaque burden is the total amount of plaque in your arteries, everywhere — not just at the single worst spot. as well; however, recent AI-QCT data suggest that the relative cardiovascular risk associated with a given increase in plaque burden is greater in women than in men.^[27,33] Women are significantly more likely to develop non-calcified, lipid-rich plaquesAn atherosclerotic lesion whose core is dominated by cholesterol esters and inflammatory lipids rather than calcium or fibrous tissue; the article notes that such plaques are highly responsive to intensive treatment and that the dramatic 65-percentage-point regression at the diagonal branch origin is consistent with reversal of a lipid-rich lesion. prone to endothelial erosion rather than fibrous cap rupture—yet both mechanisms trigger MACE. Because CAC scoring captures only the calcified component of disease, it may be a less complete risk indicator in women, who often carry a greater proportion of their total plaque burden in non-calcified form. Women with any detectable CAC face disproportionately higher relative cardiovascular risk: CAC Consortium data show approximately 1.3-fold higher hazard of cardiovascular death in women than in men at equivalent CAC burden.^[27]

In their 40s and 50s, women may accumulate a substantial burden of lipid-rich NCP that will only become radiographically detectable as calcium after the post-menopausal acceleration of vascular calcification.^[27,33] This creates a diagnostic window during midlife when traditional risk factors are rising and inflammatory plaque is accumulating, yet CAC remains at zero. The absence of calcium may be an especially incomplete risk signal precisely in this population—younger, perimenopausal women—where near-term absolute riskAbsolute risk is the real chance that something will happen to you, written as a percentage. If your absolute risk of a heart attack in the next ten years is 12 percent, that means about 12 out of every 100 people like you would have one. appears lowest but medium-term risk may be substantially higher than the calcium score suggests.

Table 4: Sex-Specific Cardiovascular Risk per Unit Plaque Volume: Selected Findings from the CONFIRM2 RegistryA large, multinational registry of over 6,000 patients in which AI-quantified coronary plaque features were evaluated for their ability to predict major adverse cardiovascular events; the registry showed that AI-derived plaque analysis improved the area under the ROC curve for event prediction from 0.62 to 0.75 compared with standard methods. (Choi et al., Circ Cardiovasc Imaging 2025 [33])

Finding — CONFIRM2 Registry (Choi et al. 2025 [33])	Women	Men
Relative risk increase per 50 mm³ total plaque volume	+17.7%  (RR ≈1.18)	+5.3%  (RR ≈1.05)
Pattern across NCP, calcified plaque, and high-risk plaque subtypes	Larger relative risk increments across all subtypes	Smaller relative risk increments across all subtypes
Principal published conclusion	Substantially higher relative cardiovascular risk per unit plaque	Lower relative risk per equivalent plaque unit

The total plaque volume risk increment (+17.7% per 50 mm³ in women vs +5.3% in men) is reported from the published CONFIRM2 results. The directional pattern across non-calcified, calcified, and high-risk plaque subtypes (larger increments in women) is the principal published conclusion of that paper; exact subtype hazard ratiosA hazard ratio compares how quickly events happen in two groups. A ratio of 0.75 means events occurred at three-quarters the rate in the treated group. should be transcribed from the published results table before any submission requiring those specific values.

Advanced Imaging: The Role of AI-Enhanced CCTA

Artificial intelligence–based quantitative CT (AI-QCT) represents a meaningful advance in non-invasive cardiovascular risk assessment. By automating measurement of total plaque burden—including calcified, non-calcified, and low-attenuation components—AI-QCT provides a more comprehensive characterization of disease than traditional CAC scoring alone.^[26,33] These tools are rapidly evolving, but broad standardization across institutions and vendors, external validation in diverse populations, sex-specific risk thresholds, and integration into clinical guidelines are still ongoing processes. AI-QCT is best understood as a promising emerging modality rather than a fully standardized replacement for current CAC and CCTA frameworks.

AI-QCT, CAC, and Reclassification in Symptomatic Cohorts

In symptomatic patients referred for clinical CCTA, research demonstrates only moderate categorical agreement between traditional CAC scores and AI-derived total plaque burden, with discordanceSee ApoB Discordance for the full entry. particularly pronounced in women.^[42] AI-QCT frequently identifies significant NCP in patients with zero Agatston scores in these referral populations. Prevalence varies widely by cohort, scanner protocol, and AI-QCT algorithm, and figures from clinical CCTA registries should not be extrapolated to general screening populations. Nonetheless, the reclassificationIn cardiovascular risk assessment, reclassification refers to the process by which an additional test — such as a CAC scan or ApoB measurement — moves a patient from one risk category to another, prompting a change in treatment decisions that a standard risk calculator alone would not have triggered. is clinically meaningful for symptomatic patients in whom a zero calcium score might otherwise prematurely terminate the diagnostic workup, especially women with additional risk features.^[26,30,42]

AI-QCT further enables quantification of high-risk plaque (HRP) features including low-attenuation plaque (LAP) and positive coronary remodeling. Data from the CONFIRM2 registry demonstrate that these features carry significantly higher relative risk in women than in men per unit of plaque volume, consistent with the clinical observation that women’s smaller-caliber coronary vessels may render each unit of high-risk plaque more hemodynamically consequential.^[33]

Integrating Epicardial Adipose Tissue Analysis

Automated analysis of epicardial adipose tissue (EAT) volume and attenuation from routine calcium-scoring CT scans has been shown to significantly enhance MACE prediction, with particularly strong incremental value in women.^[43] EAT is metabolically active and exerts paracrine pro-inflammatory and pro-atherogenic effects on adjacent coronary arteriesThe coronary arteries are the small vessels that wrap around the outside of your heart and feed the heart muscle itself. through the secretion of cytokines and adipokinesAdipokines are bioactive molecules — including leptin, adiponectin, TNF-α, and IL-6 — secreted by fat cells that act as hormones or signaling proteins to regulate metabolism, insulin sensitivity, inflammation, and energy balance throughout the body.,^[32] and integrating quantitative EAT features with CAC scoring and conventional risk factors provides a more biologically comprehensive sex-specific risk assessment than calcified plaque metrics alone, though this approach requires further standardization and prospective validation before routine clinical implementation.^[43]

An Integrated Framework for Therapeutic Mapping

A useful framework maps atherosclerosis progression through specific biological stages and identifies where different therapeutic classes exert their primary mechanistic influence. This mapping should be understood as directionally plausible based on available mechanistic and imaging data, not as a clinically proven stage-by-stage model validated by head-to-head drug-class trials.^[1,4,9]

Stages of Plaque Development and Therapeutic Positioning

Stage 1 — Endothelial Activation: Endothelial dysfunction, reduced NO bioavailability, and subendothelial retentionSubendothelial retention is the process by which ApoB-containing lipoprotein particles that have crossed the endothelial barrier become electrostatically bound to proteoglycans in the arterial intima and are unable to diffuse back into the bloodstream; it is considered the non-redundant first step in atherosclerosis under the response-to-retention framework. of apoB-containing lipoproteins. This stage is substantially modulated by endogenous estrogen and is the proposed target of early PCSK9 inhibition based on preclinical evidence.^[2,12]

Stage 2 — Early Non-Calcified Plaque: Macrophage foam cellA foam cell is an immune cell that has eaten so much trapped cholesterol that it swells up and looks foamy under a microscope. formation establishes the earliest atheromatous lesion. Bempedoic acid and statins reduce the circulating lipid pool available for subendothelial accumulation and dampen systemic inflammation.^[1,20]

Stage 3 — Intermediate / Mixed Plaque: Extracellular lipid accumulation and microcalcifications emerge within necrotic core zones. High-intensity statins and PCSK9i (when added to statins) drive plaque regressionPlaque regression means existing plaque actually gets smaller, rather than just growing more slowly. and fibrous cap maturation, with the strongest direct human trial evidence at this stage.^[1,9,14]

Stage 4 — Fibrocalcific / Stable Plaque: Dense, coalescent calcification with a thick collagen-rich fibrous cap, representing the histopathological end-state of healed plaque, associated primarily with intensive statin therapy and the calcium densification process.^[5,8,9]

Comparative Therapeutic Profile

Statins are best characterized as plaque stabilizers associated with calcium densification in observational and serial CCTA data. They have the strongest and broadest evidence base for reducing lipid-rich plaque and promoting transformation of vulnerable lesions toward denser, more stable phenotypes. A rising Agatston score under statin therapy should be interpreted in the context of documented densification and clinical improvement rather than as evidence of therapeutic failure.^[5,7,8,45]

PCSK9 Inhibitors are best characterized as plaque regressionors and fibrous cap restorers when added to statin therapy in high-risk imaging cohorts. Their principal established mechanism of clinical benefit is profound apoB/LDL lowering, with meaningful incremental plaque regression and cap thickening beyond statins alone. Pleiotropic effectsIn pharmacology, pleiotropic effects are actions of a drug that go beyond its primary intended mechanism; for incretin therapies, pleiotropic effects include anti-inflammatory activity, endothelial protection, and blood-pressure reduction that are independent of the drugs' primary glucose-lowering and weight-loss actions. suggested by preclinical data have not translated into a clear systemic anti-inflammatory signal in human outcome trials.^{[11,12,14,15]}

Bempedoic Acid functions as an upstream lipid-lowering and hsCRP-lowering agent with proven outcomes benefit in statin-intolerant patients. Its plaque-modification effects are mechanistically plausible but supported by very limited imaging data; robust serial plaque imaging evidence has not yet been reported.^[19,20,21]

Clinical Implications and Guideline Directions

The integration of pharmacologic mechanisms, advanced imaging, and sex-specific plaque biology highlights important gaps in current clinical practice and supports a shift toward biologically informed, individualized risk assessment.

Interpreting CAC = 0 in Symptomatic and Mid-Life Women

The cumulative evidence supports a calibrated interpretation of CAC = 0: it is a powerful short-term negative risk marker that should not be dismissed, yet it should not automatically end risk assessment in younger or symptomatic women—especially in the presence of early menopause, strong family historyFamily history means whether your close relatives developed heart disease, and how young they were when it happened., diabetesDiabetes is a condition where blood sugar stays too high, either because the body makes too little insulin or because it stops responding to the insulin it makes., elevated Lp(a), or persistent inflammatory risk.^[27,40,41] A CAC of 0 in a woman with these characteristics may correctly predict low 10-year event risk while substantially underestimating 15-year risk driven by ongoing non-calcified plaque accumulation and the biological effects of prolonged estrogen deficiency. In these settings, a CAC of 0 should invite further characterization of risk rather than conclude risk stratification.

A More Comprehensive Approach to Sex-Conscious Risk Assessment

A multi-modal, sex-conscious risk assessment framework incorporates several complementary elements.

Sex-specific risk factors—including age at menopause, duration of estrogen deficiency, and reproductive history—should be formally integrated into clinical risk discussions, as they carry independent prognostic weight beyond traditional Framingham-based variables.^[37,41]

Advanced imaging via CCTA should be considered when CAC scoring may underestimate true atherosclerotic burden, particularly in symptomatic women with CAC = 0 and additional risk features. The 2024 ESC Guidelines for the Management of Chronic Coronary Syndromes recommend first-line noninvasive anatomic or functional imaging for suspected CCS, selected according to pretest likelihood, patient characteristics, and local expertise. Within that framework, CCTA is specifically preferred for ruling out obstructive CAD and identifying nonobstructive disease, and the guidelines explicitly incorporate age, sex, and symptom character into pretest likelihood models.^[26,31,33]

Integrated biomarker-imaging models combining Lp(a), hsCRP, and emerging EAT fat-omics analysis represent a biologically more complete framework for sex-specific risk stratification. These approaches require further standardization and prospective validation before routine implementation.^[43]

Limitations and Open Questions

The evidence reviewed here has several important limitations that must be recognized when applying these concepts clinically or in academic scholarship.

Most plaque-imaging evidence for PCSK9 inhibitors derives from studies of add-on therapy to background statins, not from clean mechanistic comparisons between drug classes. GLAGOV, HUYGENS, and PACMAN-AMI do not establish what PCSK9 inhibitors achieve independently of statins, and their imaging endpoints cannot be directly compared with statin-only or bempedoic acid-only imaging data.^[11,14,15]

The bempedoic acid plaque-imaging literature currently consists of a single case report and one recently registered phase 3 imaging trial that has not yet reported results. Outcomes-based conclusions about bempedoic acid are well supported; morphologic plaque-imaging conclusions are not.^[24]

AI-QCT plaque detection rates vary substantially by cohort selection, referral indication, and AI-QCT protocol. Plaque prevalence figures from symptomatic CCTA referral populations should not be extrapolated to general screening populations. Standardized thresholds, validated sex-specific risk cutoffs, and prospective outcome data for AI-QCT remain incomplete.^[26,33,42]

The field still lacks clean head-to-head randomized trials designed to compare drug class effects on CAC progression or plaque morphology using sex-stratified pre-specified endpoints and the same imaging platform. The mechanistic pathways proposed for statin-associated calcium densification (Vitamin K2 inhibition, macrophage suppression) and for bempedoic acid’s anti-inflammatory effects (AMPK, possible PPARα activation) are supported primarily by preclinical evidence and remain incompletely validated in human studies.^[7,8,20,23]

Conclusion

Intensive apoB-lowering therapy reduces cardiovascular risk across drug classes, but its imaging footprints differ in important ways. Statins have the strongest and longest-established evidence for reducing lipid-rich plaque and promoting a denser, more stable calcium phenotype; their association with rising Agatston scores is best understood as calcium densification rather than uncomplicated disease progression. PCSK9 inhibitors provide additional plaque regression, lipid arc reduction, and fibrous cap thickening when added to statins, with a primarily LDL-lowering mechanism driving outcome benefit rather than a systemic anti-inflammatory one. Bempedoic acid offers proven event reduction and meaningful hsCRP lowering in statin-intolerant patients, but its effects on coronary plaque morphology remain largely unproven pending dedicated imaging trials.

CAC remains a powerful marker of calcified plaque burden and near-term prognosis, but it incompletely captures non-calcified atherosclerosis—particularly in symptomatic patients and women in mid-life. CAC = 0 should be interpreted as one component of a biologically informed risk assessment rather than as a stand-alone arbiter of disease absence. In most clinical contexts it provides powerful short-term reassurance; in specific contexts—early menopause, symptomatic presentations, elevated Lp(a), family history, or persistent inflammatory risk—it should prompt further rather than conclude risk stratification.

For women specifically, the distinct biology of plaque formation—characterized by early lipid-rich non-calcified lesions, a sensitive period of post-menopausal risk acceleration, and significantly higher relative cardiovascular risk per unit of plaque volume—demands an individualized approach to imaging and lipid-lowering therapy. A sex-conscious, multi-modal risk assessment framework incorporating CCTA, sex-specific biomarkersA biomarker is something measurable in the body that tells you about health or disease — a lab value, a scan result, a blood pressure reading., and comprehensive clinical context offers the most evidence-consistent path toward equitable and effective cardiovascular disease prevention.

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